HIV (human immunodeficiency virus) protease inhibitors have been developed for the treatment of AIDS and use of the protease inhibitors in combination with two conventional HIV reverse transcriptase inhibitors has provided further progress in the treatment of AIDS. However, these drugs and their combination use are not sufficient to eradicate AIDS, and new anti-AIDS drugs having different activities and mechanisms are therefore required.
CD4 is a known receptor from which HIV invades a target cell. Recently, CCR5 has been discovered as a second receptor of macrophage-tropic HIV. CCR5 is a G protein-coupled chemokine receptor having seven transmembrane domains. This chemokine receptor is thought to play an essential role in establishment and spread of HIV infection. In fact, it is reported that a person who is resistant to HIV infection in spite of several exposures retains mutation of homo deletion of CCR5 gene. Therefore, a CCR5 antagonist is expected to be a new anti-HIV drug.
As chemokine receptor antagonists, there are known aromatic urea derivatives (J. Biol. Chem., 1998, 273, 10095-10098.), benzodiazepine derivatives (Japanese unexamined patent publication No. 9-249570), cyclam derivatives (Nat. Med., 1998, 4, 72-77.), spiro piperidine derivatives (WO98/25604,25605,), acridine derivatives (WO98/30218), xanthene derivatives (WO98/04554), haloperidol derivatives (J. Biol. Chem., 1998,273,15687-15692., WO98/24325, 02151.), benzazocine-type compound (Japanese unexamined patent publication No. 9-25572), benzimidazole derivatives (WO98/06703), piperazine and diazepine derivatives (WO97/44329), 3-di-substituted piperidine derivatives (Japanese unexamined patent publication No. 9-249566), 4-substituted piperidine derivatives (WO99/04794), substituted pyrrolidine derivatives (WO99/09984, WO99/38514), etc. However, so far, there has been no report that a CCR5 antagonist is developed as a therapeutic agent of AIDS.